Table vi



United States Patent r 3,081,309 DERIVATIVES OF 4-(2-PROPYNYL)-4-PIPER- IDINOL AND THEIR PROCESS OF PREPA- RATION Maurice Prost, Brussels, Belgium, assignor, by mesne as- The invention relates to novel derivatives of piperidine and to a novel process for their preparation.

More specifically, the compounds of the invention are derivatives of 4-(2-propynyl)-4-piperidinol and are rep resented by the general formula:

in which R is a member of the group consisting of straight-chain aliphatic monovalent hydrocarbon radicals containing 1 to 4 carbon atoms, alkoxyalkyl, phenoxyalkyl, cycloaliphatic, and straight and branched chain alkylarornatic radicals, and R is an organic acid radical.

Salts of many of the substances covered by the above general formula have been found to have very valuable pharmacological properties. As shown by the pharmacological data given below, some of these substances exert a strong antitussive action, others are markedly analgesic, while still others possess a pronounced anesthetic action.

These pharmacological actions are unexpected when considered in the light of the observations of L. Berger, A. Ziering and J. Lee (J. Org. Chemistry, 1947, 12, p. 904). These authors found that the replacement of the phenyl group in 1-alkyl-4-phenyl-4-acyloxy-piperidines by an aliphatic hydrocarbon gave compounds of practically no activity. a

Antilussive action-This action was measured on a slightly anesthetized cat in accordance with the method of Domenjoz' (R. Domenjoz, Arch. Exp. Path. Pharmalc, 1952, 215, 19) which consists in stimulating electrically every 3 minutes the central end of the severed superior laryngeal nerve and registering on a kyrnograph the attacks of coughing thus produced. The degree of activity observed is expressed in terms of the activity of codeine. With the exception of codeine, all the substances listed hereunder were investigated in the form of the hydrochloride.

"ice

Substance Activits, codeine R R1 equals 1 CH3 0 0 OHICHF 1 OCH: I -orn c o-o on; 1

OCHa n -0 ONE: 1 -onlcnz c 0 cm 1.5 CH2CH2 co among-C} r CH(CH3)CH; c 0 onions 2 -cnicng c 0 onion: 3

The following salts of this last substance have given the results indicated below:

the mouse by means of the technique described by Hatiner (F. Hait'ner, Dtsch. Med. Wschn, 1929, 55, 731) which consists in provoking pain by pinching the base of the mouses tail with a strong artery-clip. The results of this investigation are expressed as the percentage of animals rendered insensible to pain by a dose of 50 mg./kg. of body-weight.

Substance Percentage of animals insensible to R R1 pain after Substance Percentage of animals insensible to R R pain alter 50 rug/kg.

-on (CH3) CH2@ 0 01120118 so on oni onz -CONH2 4o,

-CHa CHzO- -0 ONE, 50

Local anesthetic actiorz.-The surface anesthetic action was studied by the classical method which consists in touching the cornea of the guinea-pig with a horse-hair mounted on a glass-rod. The cornea is touched times within the space of 3.0 seconds, every 5 minutes, and note is: taken of, the number of positive reactions (absence of blinking) until the anesthetic efiect disappears. Results are expressed in terms of the activity of procaine.

The method of preparation according to the invention is characterized by the use of organo-metallic processes for obtaining 4-.(2-propynyl)-4-piperidinols and the corresponding esters.

There are three types of organo-metallic processes, i.e., the organo-magnesium method of Grignard; the organo-zinc method of Reformatzky; the organo-aluminum method described by Prevost et al. (Ch. Prevost and M. Gaudemar, C. R. Hebd. Seances Acad. Sc., 1954, 239, 282).

However, the organo-rnagnesium method of Grignard, although valid for the preparation of the new compounds covered by the above general formula, is not the most advantageous, firstly because the operations involved are more delicate and, secondly, because of the formation of undesirable by-products.

With regard to the use of the zinc process of Reformatzky, this reaction, although also valid for preparing the above-described new compounds, nevertheless presents the disadvantageous of low yield and formation of by-products.

These difiiculties have been finally overcome by the use of an aluminum amalgam as organo-metallic reaction agent which enables the reaction to be performed with the maximum yield and facility. It should be added, in this connection, that this new process which is part of the claimed invention constitutes the first application of this organo-aluminum reaction to basic ketones.

According to the claimed invention, an amalgam is prepared from turnings, granules or foils of magnesium, zinc or aluminum, to which is added 2-propyny1 halide in the presence of an ether. When the organo-metallic complex is formed, an N-substituted piperidone is added. The metallic compound is then decomposed by aqueous hydrolysis to give the carbinol which is subsequently isolated and esterified by known methods. The basic ester is then reacted with an organic or inorganic acid to form the corresponding salt.

According to a variation of this organo-metallic process, the product formed after the N-substituted piperidone is added is converted directly to an ester by reaction with the anhydride of an organic acid, the resultant basic ester being then reacted with an organic or inorganic acid to form the corresponding salt. The invention described above may be illustrated by the following nonlimitative examples:

EXAMPLE I Salts of N-Phenethyl-4-(2-Propynyl)-4-Pr0pi0n0xy- Piperidinc. (Organo-Magnesium Method) The =(2-propynyl)-magnesium bromide is prepared by stirring, at about 10 to 0 C., 4.54 g. (0.186 mole) of amalgamated magnesium in 12.5 ml. of dry ether with a solution of 22.35 g.=14.7 ml. (0.189 mole) of (2-propynyl)-bromide in 50 ml. of dry ether. The reaction lasts two hours. To the resultant product, 30.45 g. (0.15 mole) of N-phenethyl-4-piperidone dissolved in 45 ml. of dry ether are added at about 0 C. An abundant and very viscous precipitate forms. The mixture is maintained first for two hours, at about 0 C., and then, for one hour, at normal temperature. It is then cooled to about 0 C. and a solution of 45.3 g. (0.225 mole) of propionic anhydride in ml. of dry benzene is added. The reaction mixture is stirred until it returns to ordinary temperature after which it is heated for 8 hours at 60 C. on a water-bath. The mixture is decomposed with iced water, alcalinized with sodium hydroxide and saturated with salt. The ester is then extracted with benzene and the benzene solution washed with salt-saturated water. The solution is dried over anhydrous sodium sulfate, the solvent eliminated and the residue distilled under high vacuum. In this way 20.2 g. of N-phenethyl 4 (2 propynyl) 4 propionoxy piperidine are obtained. B.P.: 150 C./0.2 mm.

The hydrogen fumarate is prepared by adding the base (0.5 mole) to a warm solution of 60.3 g. (0.52 mole) of fumaric acid dissolved in 600 ml. of isopropyl alcohol. The hydrogen fumarate crystallizes on cooling. The product is filtered out, washed with a very small quantity of cold isopropyl alcohol and dried. M.P.: 191 C.

C H O N: Calculated-N=3.39%; C=6 6.48%; H: 7.03%. Found-N: 3.37%; C=66.52%; H=7.05%.

HCEC-CH: O C O czHs The following salts were prepared in a similar manner:

TABLE 1 Salts of N-phmethyl-4-(s-propynyl)-4-propionoxy-piperidine Centesimal analysis Salt Empirical M.P., Prepared Recrystallized in- Iormula 0. Additional Ele- Cale. Found Cale. ments found Hydrochloride 01911260115010 224:61 Ether.-... Ethylacetate-rnethanol 4.17 4.20 gang: 67.53

CmHzsOgNBI'. 244:1:1 Acetone... 3. 68 3. 79 Br=21. 01 21. 25

CmHrsOaNz. 141-149 ClO....' 7. 73 7. 73

CzaHaaOoN 50-55 Ether---" 2.84 2.78 C 1.09 61.01

Oxalate CnHnOtN 190-191 ..do Ethyl-acetate-methanol- 8. 59 3.56

Tartrate m C23H3iOsNH2O. 55450 Ethanol Acetone-ether 3.13 3.03 g=glos sglg Methanenesulfonate.-- omnaomsnu 169:1:1 Acetone.-. Acetone 3.54 3.51 s: 8110 e137 Hippurate onHnO Ngu 10910.5 do Ethyl-acetate 5.85 5.80

Guaiacolsulfonate CzsH3sO7NS 143:1:2 .-.(lo Acetone 2.78 2.92 S 6.36 6.45

a-NaphthalenesulIonate. CWHHOENSU--. 175 --.do Ethyl-acetateacetone..- 2.75 2.83 S= 6.31 6.52

B-Naphthalenesulfonate. C29HsaOsNS.. d Acetone 2.75 2.65 S= 6.31 6.28

d-Gamphosuli'onate..-- CH4rOtNS...' d 2.63 2.40 S 6.03 6.10

Hydrogen phthalate--- O HnOrN 3.00 2.94

EXAMPLE II commences, rises gradually to about 40 -C. It is then The bromide of (2-propyny1) zinc is prepared by mixing and stirring, at a temperature between and 45 C., 12.25 g. (0.186 mole) of amalgamated zinc in 15 ml. of

anhydrous tetrahydrofuran and 22.35 g.=l4.7 ml. (0.187

mole) of (2 -propynyl) bromide in ml. of anhydrous tetrahydrofuran. The reaction lasts 3 hours. The reaction mixture is allowed tostand overnight at room temperature. It is then cooled to about 0 C. and a solution added comprising 30.45 g. (0.15 mole) of N-phenethyl-4- piperidonein ml. of benzene. The operation of adding this solution lasts 3 hours. The mixture is then stirred for several hours until it returns to normal temperature. While still at normal temperature, 45.3 g. (0.225 mole) of propionic anhydride dissolved in 100 ml. of anhydrous benzene are added. The reaction mixture is heated for 3 hours :at C., and then allowed to stand for 2 days at normal temperaturejhe operations of separating out the end-products are the same as those described in Example I. In this way, 8.0 g. of N-phenethyl-4-(2-propynyl)-4-propionoxy-piperidine are obtained. B.P.: 132- 138 C./0.08 mm.

From this base the hydrogen fumarate is obtained which is identical to that of Example I. l

EXAMPLE III Hydrogen Fumarate of N-Phenethyli-(Z-Propynyl)-4- Propionoxypiperidine. (Organo-Aluminum Method) To a suspension of 18.4 g. (0.68 mole) of aluminum in 100 ml. of anhydrous tetrahydrofuran and 60 ml. of anhydrous benzene are added 50 mg. of mercuric chloride. Amalgamation is completed by stirring for one hour. To this suspension of aluminum amalgam are added, drop by drop, 83 ml. (1.06 mole) of (2-propynyl) bromide in 140 ml. of anhydrous benzene. The temperature of the reaction mixture is maintained between 25 and 30 C. by suitable cooling. When all the bromide is added, the solution is heated to 35 C. for one hour. It is then cooled .to about 20-25 C. and while it is maintained at this temperature a solution 0L0} g. (1 mole) of N-phenethyl-4- piperidone in 600 ml. of anhydrous benzene is slowly added. To terminate the reaction, the reaction mixture is stirred for 8 to 12 hours at normal temperature. At the end of this period, 260 g. (2 moles) of propionic anhydride dissolved in 500 ml. of anhydrous benzene are added. The temperature of the reaction mixture, which is 20 C. when the operation of introducing the propionic anhydride brought up to 5560 C. and maintained at this level for 5 to 6 hours. The residue formed when the piperidone is added dissolves gradually. The reaction mixture, while still warm, is poured into 1.5 l. of iced water. The hydrolysis solution is completed by stirring over a period of 12 hours.

While the reaction mixture is being cooled, it is alcalinized by means of a 50% solution of sodium hydroxide after which the ester is extracted several times with benzene. The benzene extracts are washed with salt water and then dried over sodium sulfate. The solution is filtered and the solvent eliminated. The residue is distilled under high vacuum. In this way, 142.0 g. of crude N- plienethyl-4-(2-propynyl) 4 propionoxy-piperidine are obtained. B.P.: 140-150 C./0.2 mm.

From this base the hydrogen fumarate is prepared which is identical to that of Example I.

EXAMPLE rv Hydrochloride of N-Aralkyl (N-Phenovcydlkyl and N- Cyclohexyl) 4-(2-Pr0pynyl) -4-Piperidin0l Esters The aluminum amalgam is prepared from 10.8 g. (0.4 mole) of aluminum, 21 m1. of anhydrous tetrahydrofuran, 50 ml. of anhydrous toluene and 50 mg. of mercuric chloride.- Under identical conditions to those described in Example III, 3.47 g. (0.6 mole) of (2-propynyl) bromide dissolved in ml. of toluene are added. When the formation of the complex is completed, 43.6 g. (0.2 mole) of N-(phenyl-Z-propyl)-4-piperidoneare introduced. After a reaction period of 3 to 4 hours, the reaction mixture is poured into iced water acidified by means of 25 ml. of acetic acid. The mixture is stirred for about 10 hours after which a 40% aqueous solution of sodium hydroxide is added until the solution is alcaline and the aluminum is completely dissolved. The carbinol is extracted with benzene and the benzene layers washed with salt water, dried over anhydrous sodium sulfate, filtered and the solvent eliminated. The residue is distilled under high vacuum. In this way, 26.2 g. of N-(phenyl-Z-propyD- 4-(2-propynyl)-4-piperidinol are obtained. BR: C./0.02 mm.

The carbinol was characterized by preparing its hydrochloride in anhydrous ether. M.P.: 179-180 C. (from ethyl acetate-methanol) C17H24ONC1: Calculated.-N=4.76%; Cl=l2.06%. Found.N=4.64%; Cl: 12.10%.

To esterify the carbinol, 7.71 g. (0.03 mole) of the carbinol obtained above, 5.19 ml. of propionyl chloride and 9.51 ml. of diethylanilinc dissolved in 50 m1. of

toluene are heated, while being stirred, over a water-bath. The mixture is heated for 18 hours at 90-95 C. After cooling, 25 ml. of water are added and the reaction mixture alcalinized with about 0.15 mol of sodium bicarbonate, after which the ester isextraeted with ether. The ethereal extracts are washed with salt water and then treated over anhydrous sodium sulfate. The solution is filtered and first the solvent and then the diethylaniline are eliminated. The residue is distilled under high vacuum. In this way, 7.0 g. of N-(phenyl-2-propyl)-4-(2- propynyl)-4-propionoxy-piperidine are obtained. B.P.: 140-l50 C./0.25 mm.

The hydrochloride is prepared in anhydrous ether by introducing hydrochloric acid gas. The reaction product recrystallizes'in acetone. M.P.: 180-188 C. (decomposition).

C H O NCI: Calculated.-N=4.00%; Cl=10.13%. Found: N=3.99%; C1=l0.30%.

TABLE II N-arallcyl, Nphpnoz yelkyl and N-cycloheyrl-(Z-propynyD-piperidinols As a variation to the above, esterification may be performed by heating the base with a reflux condenser for 5 to 8 hours with an excess of an Organic acid anhydride in the presence of a trace of concentrated sulfuric acid.

The carbinols (Table II) and corresponding esters (Table III) were prepared in a similar manner.

Bases Hydrochlorides Centcsimal analysis R Empirical Analysis, N

formula M.P.,

B.P. C./mm. C. N 01 Cale. Found Cale. Found Cale. Found CH2 C15H19ON 140-145/0.1 6.11 6. 32 183 5. 27 5. 27 13. 33 13. 39

-CI-IzCH:- CmHziON 143147/0.1 5. 5. 5. 00 5.03 12. 67 12.78

H CuHzsON. 118125/0.3 6.31 6. 41 206:!=1 5. 43 5. 61 13. 75 13. 80

-OHz-CH2'O C uHz O N. /0.3 2 5. 40 5. 65 137:l:1 4. 73 4. 86 11.98 12.16

1 M.P. 945:1 (from petroleum ether 30/40). 9 M.P. 6465 C.tron1 petroleum ether 13.1. 30 to 40 0.

TABLE III Esters of N-aralkyl, N-phenozyalkyl and N-cyclaheryl-(e-propynyD-piperidinols HCEC-CH2 0R Hydrochlorides Centcsimal analysis R R Empirical Bases, B.P.,

- formula O./mm. M.P.,

C. N Cl Cale. Found Cale. Found CH;@ -C O CzI-Is CreHmOzN 147150/O.3 4. 35 4. 37 11.01 11.10

@ -COC2H5 C 7Hz7OzN 125130/0.l5.. 1 220-230 4. 46 4. 55 11.20 11.42

-CH2CH2 C O CH: cisHziozNun 15ll54/0.35. 265 4. 35 4. 83 11.01 11.07

TABLE III-Continued Esters of N-arqlkyl, N-phenowalkyl and N-cyclohe)yl-(2-propynyl)-piperidinols Hydroehlorides Oentes'malanl R R Empirical Bases, l3.P., 1 a ysls formula O./m.m. M.P.,

Cale Found Cale. Found .(}H2()H2 COOHzGH CHs O10H2102N...- 163166/0.5.-. 186-187 4.00 4.02 10.10 10.14

OHgCHr -COOH=OHCH3 O20Hz5O2N... mouse/0.1..." 187 4.02 4.20 10.19 10.48 -oo- 02311250211 175 005 180 3.04 3.59 9.22 9.54 QH2OH3 oonom 0251190201...- 175-1s5/0.00.. 1s1+1 3.40 3.47 8.00 8.07 0 1 11, -000Em C24H2703N 188-189 3.38 3.39 8.56 8.60

-o0c,n, C19H2 O3N- 165-175/0.0. 143:1:1 3.97 4.04 10.07 10.31

Decomposed.

EXAMPLE V C H ONCI: Calculated.-N=6.87%; Cl=17.40%.

Salts of esters of N-alkyl (and N-meth0xypr0 yl).4-(2 P P y )-4piperidin0ls By the process described in Example 111 the aluminum amalgam is prepared by treating with 50 mg. of mercuric chloride a suspension of 10.1 g. (0.375 mole) of aluminum in ml. of anhydrous tetrahydrofuran and 50 ml. of anhydrous toluene. Under the same conditions as those described in example III, 66.6 g.:44 ml. (0.56 mole) of (Z-propynyl) bromide dissolved in 140 ml. anhydrous toluene are added, after which 71.2 g. (0.56 mole) of N- ethyl-piperidone-4 dissolved in 200 ml. of anhydrous 1101- none are also added. The following phases of the reaction as well as the conditions of separation are identical to those described in Example IV. In this way, 62 g. of N-ethyl-4-(2-propynyl)-4-piperidinol are obtained. B.P.: 105-110 C./10 mm.

C H ON: .Calculated. N=8.47%. Found: N: 8.46%. h r

The carbinol was characterized by preparing the hydrochloride in anhydrous ether, M.P.: 119120 C. (from ethyl acetatemethanol).

Found.--N=6.93%; Cl=17.35%. v

To esterify 8.35 (0.05 mole) of carbinol using 8.65 ml. of propionyl chloride in the presence of 12.65 m1. of dimethylaniline in 50 ml. of anhydrous toluene, the process is identical to that described in Example IV. The product is also separated in a similar manner and N-ethyl-4-(2- propynyl)-4-propionoXy-piperidine is obtained.

B.P. 131-133 C./12 mm.; hydrochloride, M.P. 172- 173 C. (from ethyl acetate and methanol).

C H O NCl: Calculated. -N=5.39%; Cl=13.65%. Found:-N=5.38%; Cl=13.56%.

L .HCI

The carbinols and esters given in Tables 1V and V were prepared in a similar manner.

TABLE IV N-alkyl and N-methozypropyZ-4-(z-propynyl)-piperidinols Bases Salts Centesimal analysis R Empirical Centesirnal formula M.P., analysis, N M.P.,

B.P., (llmm C. C. N 01 Cale. Found Cale. Found Cale. Found -CH C9H15ON. 120/20 91=b2 9. 14 9. 13 114-115 7 38 --C aH7n C11H100N 107-114/10. 59-60 7. 72 7.73 139-140 6. 43 C4H0n CmHmON" 125/0.05... 149;|=1 4. 50 -OH CHzCHzOCHa. C12HZ1O2N 103-113/0.25 104-105 4. 30

1 Hydrochloride. 2 Hydrogen lumarate.

TABLE V Esters of N-alkyl and N-methorypropyM-(Q-propynyl)-4-piperidinols) HCEC-GH2 R Hydrochlorides Centesimal analysis R R1 Empirical Bases, B.P.,

formula C./mm. h .I.,

C. N Cl Cale. Found Cale Found --C O CH: CuHnOzN" 120l2l/14 184:1:1 6. 04 6. 03 15. 30 15. 27 -COC2H5 C12H1nO2N. 125130/14. 222 5. 70 5. 75 14. 42 14. 59 C O C3H1IJ C 3Hz OzN 133137/l3 190-192 5. 39 5. 38 13. 05 13. 69 C OCH(C4H5)2 crsHzsozNn 95-100/007-.. l0l=l;l 4. 80 4. 96 12. 31 12. 3O COC(CH2)3 (314131230 130 132/15 1805:). 5. 11 5. 15 12. 94 13.07 co omH1oz. 144-14s/0.2. 19li1 4. 70 4 71 12. 00 12 14 C O CHI-Q CnHmOgN" 140-145/0.5 151:t:1 4. 54 4. 41 11.51 11.70

-COCHzCI-Iz C|3H2302N.. 145-148/0.3 1 13-14 1 4. 35 4. 20 11.01 11.12

OH; 000H20 C17Hz 03N. 150-154/0.25. 178:1:1 4.32 4 24 10. 94 10 s o113 COCaHZ(OOH3)z(3,4,5) ommtotNu =l:180/0.3. 219:21 3.04 3.67 0.23 0.34 --CsH1n 0001115 CHHMOQNH 98104/O.6. 201:1;1 5.11 5.01 12.04 13.00 -C4H0-n COC4H5 ommfiomh 150-155/13, 205-200 4.86 4.89 12.31 12.35 OH;CHgCH OCH3 COC1H O15H25O;N its/0.25 185=l=1 4.00 4.74 11.00 11.80

EXAMPLE VI C H O N Cl: Calculated.-N=9.30%; Cl=11.78%.

Carbamates of N-substituted-4-(Z-propynyl) -4-piperi- C1=11'90% dinols A solution of 8.4 g. (0.04 mole) of N-cyclohexyl-4- (2-propynyl)-4-piperidinol (cf. Table III), in 32 ml. of pyridine is cooled to 0 C. and 11.2 ml. of phenylchloroformate added, drop by drop. The reaction mixture is maintained at about 0 C. for 3 hours and then at normal temperature for 24 hours. It is then poured into iced L 391 HCEC-OE: OCONH:

water and the reaction product extracted with a mixture of ether and benzene. The extracts are washed with water and dried over anhydrous sodium sulfate and the solvent eliminated.

Tothe residue, 100ml. of methanol saturated with ammonia are added. The reaction mixture is allowed to stand for 20hours at normal temperature, after which the methanol is evaporated under vacuum. The residue is taken up with ether and washed with water.

The ethereal solution is dried over anhydrous sodium sulfate, filtered and a part of the ether eliminated. Hy-

.As a variation of the above the carbamate has been drochlonc acld gas 13 Passed thl'ough the ethfireal S0111 separated, in certain cases, in the form of a crystallized tion obtained after concentration and the hydrochloride base b y preciprtatm with etroleum eth r ft 1 of I- I-cyclohexyl-4'-(2-propynyl)-4-carbamrnoyl-piperidine ti f th th g p e a elr elmma precipitates. M.P.: 245-250 C. (decomposition) (from The carbamates listed in Table VI were re a ed a ethyl acetate-methanol). similar manner. p p r 1 a TABLE VI Carbamates ofN-rubstitutedd-(z-propynyD-4-piperidinols HCEC-CHz 000N112 Bases Hydrochlorides Oentesimal analysis R Empirical formula Centesimal M.P., analysis, N M.P.,

Cale. Found Cale. Found Cale. Found -CH2CHz- OnI-IrzOzNz 145 9.78 9.82 245:1:2 8. 67 8.61 10.98 11.07 -OH(O1I;)CH; CisHzqOzNz 215-225 8.31 8.39 10. 52 10.62

CH:; CmH1sO2N2 187 14. 27 14. 30 226 12.03 11.81 15. 23 15.14 CgI-I CnHlsogNz 194-195 13.33 13. 32 205206 11.35 11.30 14. 36 14.40 -GaH1n 01 11200 102.-. 125-126 12.48 12.30 226-227 10. 74 10.70 13.59 13.90 4H91'1 CraIIzzOQNz 207-217 10.19 10.15 12.90 13.08 CH CH CH OOH3 CrsHzzOaNg 182-:|:2 9. 62 9.60 12.19 12.25

-o1r2-cn2 0- 017112201203 189:1:1 8.29 8.42 10.46 10.77

1 Decomposed.

EXAMPLE VII Hydrochloride of the phenylcarbamate of N-methyl-4- (Z-propynyl)-4-piperidinol To a solution of 0.3 g. of zinc acetate and 7.65 g. (0.05 mole) of Nqmethyl-4-(2-.propynyl)-4-piperidinol (cf. Table IV) in m1. of chloroform are added 6.0 g. (0.05 mole) of phenyl isocyanate. The reaction mixture is allowed to stand for 5 days at normal temperature after which it is refluxed for 4 hours. The last traces of isocyanate are then eliminated under vacuum, the residue HCEC-CE: O C ONE-CaHi L .HCl

N in. EXAMPLE VIII Hydrogen fumarate of N-phenethyl-4- (2-propynyl)-4- propionoxy-piperidine To a suspension of 4.0 g. (0.148 mole) of aluminum in ml. of anhydrous tetrahydrofuran are added mg. of mercuric chloride. The amalgamation is terminated by stirring for 1 hour. To this aluminum amalgam suspension are added 2 ml. of (2-propynyl) bromide. When the complex begins to form, 50 ml. of diethylene-glycoldiethylether are introduced and then 14.8 ml. (total 16.8 ml.=0.22 mole) of (Z-propynyl) bromide dissolved in 50 ml. of diethyleneglycol-diethylether are added, drop by drop, at a temperature of 20 to 27 C. When the bromide has all been added the reaction mixture is allowed to stand 3 to 4 hours at normal temperature. A solution of 40.6 g. (0.2 mole) of N-phenethyl-4-piperidone dissolved in 100ml. of diethyleneglycol-diethylether is then added at a temperature of 20 to 27 C. A yellowish precipitate is seen to form. To terminate the reaction, the mixture is stirred for 8 to 12 hours at normal temperature, after which 250 m1. of anhydrous benzene are added, the reaction mixture is cooled to about 5 C. and while this operation is maintained 41.6 rnl. of propionic anhydride are introduced. The reaction mixture is allowed to stand until it returns to normal temperature, after which it is heated for 12 to 14 hours at 40-45 C. The operations of separation are identical to those described in Example 111. Thus, 37.2. g. of crude N-phenethyl-4-(2-propynyl)-4-propionoxy-piperidine are obtained (B.P.: 135-145 C./0.07 mm). After separation of the reaction product, 75% to 80% of the diethyleneglycol-diethylether may be recuperated.

From this base, the hydrogen fumarate is prepared which is identical to the product obtained in Example 1. Instead of diethyleneglycol-diethylether, diethyleneglycoldimethylor dibutylether, triethyleneglycol-diethylether or ethyleneglycol-diethylor dimethylether may be employed.

What is claimed is:

1. A compound of the class consisting of a free base and the pharmaceutical'ly acceptable acid addition salts thereof, the free base represented by the formula:

of methyl, ethyl, propyl, butyl, 3-methoxypropyl, phenoxyethy l, cyclohexyl, benzyl, phenethyl and a-rnethyl phenethyl and R is a radical selected from the group consisting of acetyl, propionyl, butyryl, diethyl acetyl, trimethylacetyl, crotonyl, benzoyl, trimethoxybenzoyl, phenylacetyl, B phenylpropionyl, phenoxyacetyl and carbamyl.

2. N-phenethyl-4 2-propynyl l-propionoxy-piperidine.

3. The pharmaceutically acceptable non-toxic acid addition salts of N-phenethylt(2 propynyl)-4apropionoxypiperidine.

4. N-(phenyl-Lpropy-D-l-(Z propynyl)-4-propionoxypiperidine.

5. The pharmaceutically acceptable non-toxic acid addition salts of N-(phenyl-Z-propyl)-4-(2-propynyl)-4- propionoxy-piperidine.

6. N-phenethyl-4-(21propynyl)-4-acetoXy-piperidine.

7. The pharmaceutically acceptable non-toxic acid addition salts of Nphenethyl-4-(2+propynyl)-4-acetoxypiperidine.

8. N-methyl-4-( 2 propynyl') -4 phenoxyacetoXy-1piperidine.

9. The pharmaceutically acceptable non-toxic acid addition salts of N-methyl-4-(2apropynyl)-4-phenoxyacetoxy-piperidine.

10. Process for the preparation of a compound represented by the formula:

HCEC-CH: R

in which R is a radical selected from the group consisting of methyl, ethyl, propyl, butyl, B-methoxypropyl, phenoxyethyl, cyclohexyl, benzyl, phenethyl and a-methyl phenethyl and R is a radical selected from the group consisting of acetyl, prepionyl, butyryl, diethyl acetyl, trimethyla'cetyl, lcrotony l, benzoyl, trimethoxybenzoyl, phenylacetyl, fi phenylpropionyl, phenoxyacetyl and carbamyl, wherein a (2-propynyl) halide is reacted in the presence of an ether with a compound selected from the group consisting of magnesium, aluminum and zinc, the resultant organza-metallic complex reacted with an N-substit-uted piperidone and the metallo-halide derivative of propynylpiperidinol obtained is decomposed by an organic acid anhydride to form the basic ester.

'11. Process according to claim 10, wherein the (2-propynyl). halide is (Z-propynyl) bromide.

12. Process according to claim 10, wherein the metallohalide derivative of propynyl-lpiperidinol is decomposed by aqueous hydrolysis and the isolated propynyl-piperidinol subsequently reacted with an acylating agent selected from the group comprising organic acid halides and organic acid anhydrides to form the basic ester.

References Cited in the file of this patent UNITED STATES PATENTS 2,739,963 Sperber et a1 Mar. 27, 1956 2,838,518 Schuler June 10, 1958 2,880,211 Elpern Mar. 31, 1959 OTHER REFERENCES Nazarov et al.: Chemical Abstracts, vol. 52, page 17258 (1958). 

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, THE FREE BASE REPRESENTED BY THE FORMULA:
 2. N-PHENETHYL-4(2-PROPYNYL) -4-PROPIONOXY-PIPERIDINE.
 3. THE PHARMACEUTICALLY ACCEPTABLE NON-TOXIC ACID ADDITION SALTS OF N-PHENETHYL-4(2-PROPYNYL)-4-PROPIONOXYPIPERIDINE. 